Although significant progress has been made recently in hepatitis B (HBV) therapy, the current knowledge in the management of HBV infection is limited because treatment trials have utilized one to two years of therapy at most, whereas most patients require treatment of much longer duration for optimal long term outcome. Our first project addresses optimal long term management of patients with HBeAg-positive chronic hepatitis B. Thus, in Project 1, we propose a trial in patients with HBeAg-positive chronic hepatitis to evaluate the ability of pegylated interferon in combination with tenofovir (TDF) to alter the natural history, by achieving the following aims: (Project 1a) to compare the long term efficacy and safety of combination of pegylated interferon and TDF versus TDF alone and (Project 1 b) to identify predictors of response to the combination therapy and measure the long term benefit of antiviral therapy. In our second project, we will investigate means to optimize the long term outcome in patients with HBV infection including HCC and end stage liver disease. The majority of these patients will be HBeAg-negative. These patients are in a later phase of chronic HBV infection and thus tend to be older and to have more fibrosis, which predispose them to a higher risk of developing hepatocellular carcinoma (HCC). Thus, in Project 2, we propose observational studies to dissect the effect of host (e.g., age, gender, race, stage of liver disease) and virologic (genotype, sequential HBV DMA levels) characteristics on the risk of HCC, by conducting studies with following aims: (Project 2a) to compare the age- and gender-specific incidence of HCC between patients of Asian and African origin and (Project 2b) to measure the effect of baseline patient characteristics and serial HBV DMA and ALT levels to develop a score estimating the risk of HCC and assess the impact of antiviral therapy on the risk of developing end stage liver disease and HCC. While the most active liver disease tends to be seen in young, HBeAg-positive hepatitis patients, the majority of our clinic patients are HBeAg-negative with little evidence of active liver disease. Our project addresses important questions in both of these populations.